EP1531837A1 - Compositions et procedes pour la prophylaxie et le traitement des ulceres aphteux et des lesions dues a l'herpes - Google Patents

Compositions et procedes pour la prophylaxie et le traitement des ulceres aphteux et des lesions dues a l'herpes

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Publication number
EP1531837A1
EP1531837A1 EP02739785A EP02739785A EP1531837A1 EP 1531837 A1 EP1531837 A1 EP 1531837A1 EP 02739785 A EP02739785 A EP 02739785A EP 02739785 A EP02739785 A EP 02739785A EP 1531837 A1 EP1531837 A1 EP 1531837A1
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EP
European Patent Office
Prior art keywords
medicament
mammal
magnesium
lesion
compound
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP02739785A
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German (de)
English (en)
Other versions
EP1531837A4 (fr
Inventor
Win L. Chiou
Linda L. Chiou
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Chiou Consulting Inc
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Chiou Consulting Inc
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Publication of EP1531837A1 publication Critical patent/EP1531837A1/fr
Publication of EP1531837A4 publication Critical patent/EP1531837A4/fr
Withdrawn legal-status Critical Current

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
    • A61K9/0056—Mouth soluble or dispersible forms; Suckable, eatable, chewable coherent forms; Forms rapidly disintegrating in the mouth; Lozenges; Lollipops; Bite capsules; Baked products; Baits or other oral forms for animals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K33/00—Medicinal preparations containing inorganic active ingredients
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
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    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/191—Carboxylic acids, e.g. valproic acid having two or more hydroxy groups, e.g. gluconic acid
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    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/194—Carboxylic acids, e.g. valproic acid having two or more carboxyl groups, e.g. succinic, maleic or phthalic acid
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    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/20—Carboxylic acids, e.g. valproic acid having a carboxyl group bound to a chain of seven or more carbon atoms, e.g. stearic, palmitic, arachidic acids
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    • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • A61K31/57—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane or progesterone
    • A61K31/573—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane or progesterone substituted in position 21, e.g. cortisone, dexamethasone, prednisone or aldosterone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A61K31/60—Salicylic acid; Derivatives thereof
    • A—HUMAN NECESSITIES
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    • A61K33/06—Aluminium, calcium or magnesium; Compounds thereof, e.g. clay
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    • A61K33/14—Alkali metal chlorides; Alkaline earth metal chlorides
    • A—HUMAN NECESSITIES
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    • A—HUMAN NECESSITIES
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    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
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    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0014—Skin, i.e. galenical aspects of topical compositions
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
    • A61K9/006—Oral mucosa, e.g. mucoadhesive forms, sublingual droplets; Buccal patches or films; Buccal sprays
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
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    • A61K9/0063—Periodont
    • A—HUMAN NECESSITIES
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    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/02—Stomatological preparations, e.g. drugs for caries, aphtae, periodontitis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/02—Drugs for dermatological disorders for treating wounds, ulcers, burns, scars, keloids, or the like
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/04—Centrally acting analgesics, e.g. opioids
    • A—HUMAN NECESSITIES
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    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
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    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/20—Antivirals for DNA viruses
    • A61P31/22—Antivirals for DNA viruses for herpes viruses

Definitions

  • Canker sores are a common oral lesion. Approximately 20% of the population will suffer from the annoyance and irritation of a canker sore in their lifetime. (Gastrointestinal Disease: Pathophvsiology/Diagnosis/Management. 5th edition, M. H. Sheisenger et al., eds., W.B. Saunders Company, Philadelphia, p. 273 (1992).) Canker sores are generally round, clearly defined, painful, shallow ulcers in the lining of the mouth (oral mucosal surfaces).
  • ulcers/canker sores usually begin with a tingling or burning sensation (prodromal period), followed by a red spot or bump (a swelling of the tissue) that ulcerates.
  • the ulcers/canker sores are often covered with a grayish- white exudate and surrounded by an erythematous (inflammatory) margin. They range in size from pinpoint (minor aphthae) to over one-quarter inch in diameter (major aphthae).
  • Canker sores usually cause discomfort and/or pain, and they may cause pain so severe that difficulties in speaking and eating result, which can lead to weight loss.
  • Canker sores usually last from about 7 to about 10 days, but may last for several weeks.
  • canker sores The cause of canker sores is unknown, but a number of conditions are believed to be associated with the disorder, suggesting that more than one cause is likely. Some canker sores are thought to be related to an abnormal immune system and are probably genetically influenced. Emotional stress and mouth injury, such as those caused by dental procedures, aggressive tooth cleaning or local trauma, such as when the tongue or cheek is bitten, are thought to trigger outbreaks. Further etiologic factors include immunologic, microbiologic, viral, nutritional factors, such as dietary deficiencies (especially iron, zinc, folic acid or vitamin B 12 ), menstrual periods, hormonal changes and food allergies (to substances in nuts, chocolate, acidic foods (such as vinegar, pickles or citrus) and glutin). (Oral Pathology: Clinical Pathologic Correlations. 3rd edition, J. A. Regezi et al., eds., W.B. Saunders Company, Philadelphia, pp. 46-53 (1999).)
  • amlexanox oral paste 5% (Aphthasol® from Block Drug Company) was made available as a prescription drug to treat aphthous ulcers.
  • its efficacy is still quite limited. For example, after 4 days (four times daily) of continuous treatment, complete resolution of pain and complete healing of ulcers was achieved in only 60% and 37% of patients, respectively.
  • U.S. Patent No. 5,981,499 by Hau discloses a topical method to deliver a supratherapeutic level of antibiotic to shallow aphthous ulcers to inhibit opportunistic pathogenic bacteria in the oral mucosa that is substantially higher than levels achieved by oral, intramuscular or intravenous administration of antibiotic.
  • the medicament is in the form of a powder or troche and includes a dry dosage of antibiotic such as one of the known penicillins, beta-lactam antibiotics, tetracyclines, aminoglycosides, cephalosporins, macroglides, vancomycin, bacitracin, chloramphenicol and their salts and mixtures thereof.
  • the powder or troche includes an effective amount of a salt or oxide of a polyvalent metal compound such as magnesium, zinc, calcium, aluminum, bismuth, titanium, and copper and mixtures thereof to form a protective barrier over the aphthous ulcer.
  • a salt or oxide of a polyvalent metal compound such as magnesium, zinc, calcium, aluminum, bismuth, titanium, and copper and mixtures thereof to form a protective barrier over the aphthous ulcer.
  • the presence of the antibiotic prevents most microorganisms of the normal flora from surviving or multiplying, permitting tissue regeneration processes to occur under the protective barrier coating.
  • control of infection is essential for promoting the healing process.
  • the troche or powder may be mechanically directed in place, for example, by the fingers. Once in contact with the aphthous ulcer, the troche or powder may be held in position by the tongue for about 5 to 15 minutes.
  • painful symptoms improve 24 hours after treatment, ulcers display visible signs of healing within 2 days, and canker sores heal in about two to
  • Hau the methods disclosed by Hau are limited in several ways. For example, it can be difficult or impossible to hold the dosage form for 5 to 15 minutes in hard-to-access areas of the mouth. Additionally, administration can be difficult or impossible in most infants and small children. Another serious drawback of the methods disclosed by Hau are that some patients may be allergic to antibiotics. Also, the development of antibiotic-resistant microorganisms can occur as a result of the methods of Hau. Another type of common lesion is caused by the herpes simplex virus
  • HSN herpes simplex virus
  • HSV-1 herpes simplex virus
  • Symptoms of HSN- 1 infection occur mainly in the pharynx, intraoral sites, lips, eyes and skin above the waist, while those of HSN-2 occur mainly on the genitalia and the skin below the waist.
  • the most common recurring site for HSN-1 is the vennilion border and adjacent skin of the lips, known as herpes labialis ("cold sore" or "fever blister").
  • An oral HSN outbreak occurs in about 15 to about 45 percent of the population (Neville et al., p. 183). Usually, from about 6 to about 24 hours before the lesions develop, prodromal symptoms appear (such as pain, burning, itching, tingling, a localized warmth and erythema of the involved area; these symptoms being referred to as "pre-ulceration” or "prelesion” symptoms of herpes simplex lesion herein). Multiple small, erythematous papules may develop and form clusters of vesicles. The vesicles may rupture and crust in about 2 days. Abolishment of pain and healing of ulcer, or lesion usually occurs within about 7 to about 10 days.
  • Topical pastes or gels containing certain specific analgesics such as benzocaine or benzyl alcohol have been commonly available as over-the-counter products to temporarily relieve the pain of the disease.
  • Abreva® docosanol
  • GlaxoSmith line Pharmaceutical Company was reported to perform only slightly better than the placebo (mean healing time of 4.1 days versus 4.7 days for placebo in one study) in treating cold sores (The Wall Street Journal, January 19, 2001).
  • Prescription products containing topical antiviral drugs, such as Denavir® (penciclovir cream) were also reported to be of limited value in treating herpes simplex lesions (The Wall Street Journal, January 19, 2001).
  • compositions and methods represent the hitherto most safe and efficacious prophylaxis and treatments (including abolishment of pain and inflammation as well as regeneration of ruptured tissue) of pre-ulcerous/lesion symptoms, aphthous ulcers and herpes simplex lesions.
  • ionic and nonionic (neutral) moieties of the polyvalent metals are pharmacologically active.
  • the present invention provides for the use of an effective amount of a salt or oxide of one or more polyvalent metals to prepare a medicament (a medicinal substance or agent that treats or prevents or alleviates a medical condition such as a disease and/or its symptoms) useful for: preventing an aphthous ulcer on a mucosal surface of a mammal; treating an aphthous ulcer on a mucosal surface of a mammal wherein the medicament comprises a mucoadhesive paste; treating one or more pre-ulceration symptoms of an aphthous ulcer on a mucosal surface of a mammal; treating a herpes simplex lesion on the skin of a mammal wherein the polyvalent metal is not zinc; or preventing a herpes simplex lesion on the skin of a mammal wherein the polyvalent metal is not zinc.
  • a medicament a medicinal substance or agent that treats or prevents or alleviates a medical condition such as a disease and/or its
  • the present invention also provides a method for preventing an aphthous ulcer on a mucosal surface of a mammal comprising topically administering an effective amount of a salt or oxide of one or more polyvalent metals to a mucosal surface demonstrating pre-ulceration symptoms so as to prevent the ulcer.
  • the present invention further provides a method for treating an aphthous ulcer on a mucosal surface of a mammal comprising topically administering an effective amount of a salt or oxide of one or more polyvalent metals in a mucoadhesive paste to the ulcer.
  • the present invention also provides a method for treating one or more pre-ulceration symptoms of an aphthous ulcer on a mucosal surface of a mammal comprising topically administering an effective amount of a salt or oxide of one or more polyvalent metals to a mucosal surface demonstrating pre- ulceration symptoms.
  • the present invention provides a method for treating a herpes simplex lesion on the skin of a mammal comprising topically administering an effective amount of a salt or oxide of a polyvalent metal to a mammal in need of such treatment, where the polyvalent metal is not zinc.
  • a method for preventing a herpes simplex lesion on the skin of a mammal comprising topically administering an effective amount of a salt or oxide of a polyvalent metal to an area of skin demonstrating pre- lesion symptoms so as to prevent the lesion, where the polyvalent metal is not zinc.
  • the invention also provides a method for preventing an aphthous ulcer or herpes simplex lesion in a mammal comprising topically administering an effective amount of one or more anti-inflammatory compounds (steroidal and or nonsteroidal) with or without an effective amount of a salt or oxide of one or more polyvalent metals to the affected mucosal or skin surface likely to suffer from an aphthous ulcer or herpes simplex lesion.
  • an anti-inflammatory compound such as hydrocortisone acetate
  • a polyvalent metal compound potentiates the activity of the metal compound and reduces the chance of flare-ups of lesion.
  • a novel ultra-low-strength of hydrocortisone such as 0.02% is unexpectedly found to be therapeutically highly effective (Example XIX). Strengths of 1.0% and 2.5% in ointments or creams are commonly available for external use.
  • the invention also provides the use of an effective amount of a salt or oxide of one or more polyvalent metals to prepare a medicament useful for: preventing or treating oral ulcers of a mammal resulting from chemotherapy or radiation therapy; or providing relief of pain and wound healing of burned tissue of a mammal.
  • the present invention also provides a method for the prophylaxis or treatment of oral ulcers of a mammal resulting from conventional chemotherapy and radiation therapy (e.g., cancer treatment therapy) comprising topically administering an effective amount of a salt or oxide of one or more polyvalent metals to a mucosal surface likely to suffer or suffering from ulcer formation.
  • conventional chemotherapy and radiation therapy e.g., cancer treatment therapy
  • the present invention also provides a method for providing relief of pain, inflammation, infection and the promotion of wound healing of burned tissue, as a result of fire or heat of a mammal comprising topically administering an effective amount of a salt or oxide of one or more polyvalent metals to the affected burned tissue.
  • an effective amount ranging from about 0.1% to about 2% preferred
  • an effective amount of one or more polyvalent metals is administered in a solution, a liquid, a spray, or a gel, containing at least 30% by weight of glycerin, that will serve as an effective liquid protective layer for the burned tissue.
  • compositions and methods described herein provide the following benefits: (1) rapidly (within about 5 minutes to about 15 or about 20 minutes) inhibit or stop the tingling or burning sensation associated with an oral aphthous ulcer or an oral pre-ulcerous area of the mouth after a single application; (2) rapidly (within minutes) abolish the pain and irritation of an inflammatory red spot or erythematous bump (pre-ulceration symptoms) of the oral tissue after a single application; (3) completely cure the inflammatory red spot or erythematous bump (associated with pre-ulceration of the oral mucosa) of oral tissue after about one to about five applications and within about 24 hours from the beginning of treatment; (4) quickly (within minutes) stop the pain associated with an inflammatory aphthous ulcer after a single application; (5) completely cure/heal the ulcerated inflamed tissue of an aphthous ulcer after about one to about five applications of the medicament within about 12 hours to about 24 hours; (6) do not require a physician's prescription; (7) are virtually free of allergic
  • the present invention includes methods to generally abolish the pain associated with pre-ulceration (e.g., stinging or burning sensation, painful red spots, painful erythematous bumps and mouth injury) and post-ulceration conditions (e.g., painful and inflammatory lesions/ulcerated skin and/or ulcerated mucosal surfaces) of aphthous ulcers or herpes simplex lesions of a human after one application of a medicament comprising an effective amount of one or more salts or oxides of polyvalent metals.
  • the present invention also includes methods to rapidly (within about 12 hours to about 24 hours) heal an inflamed aphthous ulcer.
  • the medicaments of the invention include, for example, an effective amount of one or more polyvalent metal compounds, such as magnesium sulfate, without or preferably with an anti- inflammatory compound, such as hydrocortisone acetate.
  • the medicaments comprise a mucoadhesive agent to form a mucoadhesive paste.
  • the medicaments and methods of the invention are also effective to treat and/or prevent herpes simplex lesions (see Example XN-QI), oral ulcers resulting from chemotherapy or radiation therapy (e.g., cancer treatment therapy), and to treat tissue which has been burned by fire or heat.
  • the term "lesion” or “ulcer” includes lesions or ulcers of the lips and adjacent skin, the tongue, the gums and other internal tissues of the oral cavity, and the pharynx.
  • the lesion or ulcer can be an aphthous ulcer, an aphthous-like ulcer, a lesion of the pharynx, or a lesion associated with herpes simplex virus, gingivitis or stomatitis.
  • the lesion or ulcer can be of the mucosal, submucosal, epidermal, dermal and/or subcutaneous tissue.
  • Treating includes ameliorating the symptoms of, curing, and preventing the development of a given disease or condition.
  • the disease or condition to be treated or prevented is an aphthous ulcer or a herpes simplex lesion.
  • prevention includes the prevention (i.e., prophylaxis) of ulceration in an area demonstrating pre- ulceration symptoms.
  • pre-ulceration symptom(s) of aphthous ulcers refers to stinging, burning, pain, inflamation, red spots, erythematous bumps and mouth injury prior to the formation of ulcers in the mouth.
  • post-ulceration symptoms refers to the pain, inflammation and ruptured tissue of the ulcer or lesion.
  • bioadhesive refers to a substance, such as a paste or biologically compatible cement, that provides or promotes adhesion to a biological surface.
  • mucoadhesive refers to a substance, such as a paste or biologically compatible cement, that provides or promotes adhesion to mucosal surfaces.
  • Bioadhesive and mucoadhesive agents include, but are not limited to, carboxymethylcellulose or derivatives thereof, Carbopol ® ULTREX- 10 (a polyacrylic acid polymer used as a thickening, bioadhesive or mucoadhesive agent), polyacrylic acid polymer, gelatin or a mixture thereof.
  • the bioadhesive substance and/or the mucoadhesive substance will allow for prolonged (about 1 to about 8 hours) direct contact between the tissue (biological surface) and the medicinal composition, and thus, allow for a continuous and effective delivery system.
  • the phrase "thickening agent” refers to any substance/material used to thicken a medicinal composition. Thickening agents include, but are not limited to, carboxymethylcellulose or derivatives thereof, Carbopol ® Polymers, polyacrylic acid polymer, gelatin or a mixture thereof.
  • the phrase "effective amount” refers to that amount of a compound which is sufficient to effect treatment when administered to a mammal in need of such treatment or prevention.
  • polyvalent metal compound refers to any organic or inorganic polyvalent metal compound that has the beneficial therapeutic properties described herein.
  • Polyvalent metal compounds include bismuth compounds, zinc compounds, magnesium compounds, aluminum compounds, calcium compounds, titanium compounds, iron compounds, copper compounds or a barium compounds.
  • the polyvalent metal is not aluminum.
  • the polyvalent metal is not a Group ⁇ ia element, such as boron, aluminum, gallium, indium, or thallium.
  • polyvalent metals have beneficial properties including analgesic, anti-inflammatory, anti-microbial and tissue- regenerating properties for controlling, preventing, or treating pre-ulceration and/or post-ulceration symptoms related to aphthous ulcers and/or herpes simplex lesions.
  • an amount of a polyvalent metal effective to produce the stated therapeutic activity is administered.
  • the counterion to the metal does not contribute significantly to the stated therapeutic effect.
  • the term "polyvalent metal salt” preferably excludes salts wherein the counterion to the metal would contribute significantly to the stated therapeutic effect when administered according to the method of the invention.
  • the "polyvalent metal salt” is an inorganic or organic salt or complex. In another embodiment of the invention, the “polyvalent metal salt” is an inorganic salt.
  • water-soluble (solubility greater than 1 in 50) polyvalent metal compounds such as magnesium sulfate and ferric chloride
  • water-insoluble (solubility less than 1 in 1,000) polyvalent metal compounds such as bismuth citrate and magnesium hydroxide
  • ionic and nonionic species of the polyvalent metals are therapeutically effective.
  • the therapeutically effective compound is selected from the group consisting of bismuth, bismuth subsalicylate, bismuth chloride, bismuth oxide, bismuth subcarbonate, bismuth subgallate, bismuth subnitrate, bismuth phosphate, bismuth aluminate, bismuth salicylate, bismuth tribromophenate, bismuth dipropylacetate, bismuth citrate, bismuth sub mecanicte, bismuth ascorbate, bismuth subcarbonate, bismuth tartrate, and colloidal bismuth subcountrye.
  • Pepto-Bismol ® and Bismatrol ® are examples of compositions that comprise a bismuth compound.
  • the therapeutically effective compound is selected from the group consisting of zinc, zinc sulfate, zinc acetate, zinc gluconate, zinc chloride, zinc carbonate, zinc oxide, zinc oleate, zinc stearate, zinc propionate, and zinc undecenoate.
  • the therapeutically effective compound is selected from the group consisting of magnesium, magnesium acetate, magnesium ascorbate, magnesium carbonate, magnesium chloride, magnesium citrate, magnesium stearate, magnesium gluconate, magnesium hydroxide, magnesium salicylate, magnesium sulfate and magnesium oxide.
  • the therapeutically effective compound is selected from the group consisting of aluminum, aluminum acetate, aluminum carbonate, aluminum chloride, aluminum potassium sulfate, aluminum glycinate, aluminum hydroxide, aluminum lactate, aluminum oxide, aluminum subacetate, aluminum sulfate and aluminum phosphate.
  • the therapeutically effective compound is selected from the group consisting of calcium, calcium acetate, calcium alginate, calcium benzoate, calcium carbonate, calcium chloride, calcium citrate, calcium gluconate, calcium hydroxide, calcium lactate, calcium phosphate, calcium stearate, calcium sulfate and calcium oxide.
  • the therapeutically effective compound is selected from the group consisting of copper, copper gluconate and copper sulfate.
  • the therapeutically effective compound is selected from the group consisting of titanium, titanium dioxide, titanium peroxide, titanium salicylate and titanium tannate.
  • the therapeutically effective compound is selected from the group consisting of iron, ferric chloride, ferric citrate, ferric oxide, ferrous ascorbate, ferrous carbonate, ferrous sulfate, ferrous gluconate, ferrous fumarate, ferrous glycine sulfate and ferrous lactate.
  • the therapeutically effective compound is selected from the group consisting of barium, barium carbonate, barium chloride, barium hydroxide and barium sulfate.
  • the polyvalent metal compound is magnesium (e.g., magnesium sulfate).
  • magnesium e.g., magnesium sulfate
  • Applicant has found magnesium to be very effective in treating and preventing aphthous ulcers or herpes simplex lesions, in treating pre-ulceration or pre-lesion symptoms, such as pain and inflammation, and in treating post-ulceration or post-lesion symptoms.
  • magnesium possesses many preferred characteristics for polyvalent metals for use in the present invention, such as pleasant to taste, colorless, odorless, endogenous, non-toxic, non-irritating, inexpensive, and stable.
  • the polyvalent metal compounds can be formulated as pharmaceutical compositions and administered topically to a human patient in a variety of forms, including gels, ointments, creams, pastes, lotions, liquids (e.g., oral rinses such as mouth washes/rinses), a lozenge, a medicated bandage, a spray or any other form which is suitable for topical and effective administration to an oral or percutaneous ulcer/lesion.
  • forms including gels, ointments, creams, pastes, lotions, liquids (e.g., oral rinses such as mouth washes/rinses), a lozenge, a medicated bandage, a spray or any other form which is suitable for topical and effective administration to an oral or percutaneous ulcer/lesion.
  • the polyvalent metal compounds may be applied in pure form. However, it will generally be desirable to administer them to the mucosal surface or skin as compositions or formulations in combination with a suitable dermatologically or pharmaceutically acceptable carrier, which may be a solid or a liquid.
  • a suitable dermatologically or pharmaceutically acceptable carrier includes any dermatologically or pharmaceutically acceptable carrier which is capable of mixture with a polyvalent metal compound.
  • Useful solid carriers include carboxymethylcellulose or derivatives thereof, Carbopol® polymers, polyacrylic acid polymer, gelatin or a mixture thereof.
  • Useful liquid carriers include water, glycerin, alcohols or glycols or water-alcohol/glycol blends, in which the present compounds can be dissolved or dispersed at effective levels, optionally with the aid of non-toxic surfactants.
  • the resultant liquid compositions can be applied from absorbent pads, used to impregnate bandages and other dressings, sprayed onto the affected area using pump-type or aerosol sprayers, or used as mouth rinses.
  • the medicament which is administered to a patient comprises a polyvalent metal compound and a bioadhesive or mucoadhesive paste.
  • dosage forms that comprise bioadhesives and/or mucoadhesives provide prolonged (about 1 hour to about 8 hours) direct contact with the damaged and/or diseased (e.g., pre-ulcerous and/or post- ulcerous) tissue area.
  • a spatula e.g., applicator
  • the spatula or similar device can facilitate application or administration of the paste, gel or ointment, especially in areas difficult to reach by inserting the finger.
  • the spatula or similar device can be made of metal, plastic, or wood.
  • the applicator is more hygienic and may perform better than a finger in administering or spreading the product (e.g., the paste, gel or ointment) to the lesion in all areas.
  • Drying of the tissue area of lesion with a clean paper, tissue, cotton tip, or gauze before admimstration of a medicament of the invention can facilitate close contact, maintain high drug concentrations at the lesion site and hence enhance the efficacy of the treatment.
  • patients should have the mouth open slightly in a lying down, sitting or standing position. With the mouth open, the saliva produced can more easily flow directly into the stomach without accumulation in the mouth cavity.
  • the patient When using a liquid mouth rinse/wash, the patient should first swirl the medicament in the mouth for several seconds (to ascertain contact between the medicament and the surface of the lesion) and hold the medicament in the mouth for as long as possible (from a few minutes to about 10 minutes) by closing the mouth. After spitting out the diluted medicament, the patient should not drink or eat for about 30 to about 60 minutes to allow a longer time of contact between the medicament and the surface of the lesion in the mouth. To enhance the contact time between the medicament and the surface lesion, a viscosity- enhancing agent, such as Carbopol®, glycerin and carboxymethylcellulose or a derivative thereof, may also be incorporated into the mouth rinse. A fragrance, coloring agent and/or a preservative may also be added to the mouth rinse, h a preferred embodiment, a patient is first treated with a mouth rinse and then treated with a paste application.
  • Carbopol® Carbopol®
  • glycerin and carboxymethylcellulose or a derivative thereof may
  • Suitable methods for preparing gels, ointments, creams, pastes, lotions, liquids e.g., oral rinses such as mouth washes/rinses), lozenges, medicated bandages, or sprays suitable for topical and effective administration to an oral or percutaneous ulcer or lesion or to an area demonstrating pre-ulcerous or pre- lesion conditions are known in the art and are illustrated in the Examples.
  • the concentration of a polyvalent metal compound in a liquid, semi-solid, or solid composition will be about 0.01% to about 10%, preferably about 0.1% to about 10%, more preferably about 0.01% to about 3.5%, more preferably 0.03% to about 2.5%, and more preferably about 0.05% to about 2.0% weight by volume, hi a preferred embodiment the polyvalent metal compound(s) is present in the pharmaceutical compositions/medicaments in amounts ranging from about 0.01% to about 30%, preferably from about 0.02% to about 3% weight by volume.
  • an anti-inflammatory compound is administered in combination with a polyvalent metal compound.
  • Anti- inflammatory compounds include glucocorticoidal steroids such as hydrocortisone, prednisolone, dexamethasone, or triamcinolone acetonide, as well as nonsteroidal anti-inflammatory drugs (NSAlDs), such as salicylate, ibuprofen, naproxen, acetominophen, indomethocin or ketoprofen.
  • the anti-inflammatory compound is hydrocortisone or hydrocortisone acetate.
  • the inclusion of an anti-inflammatory compound markedly enhances the therapeutic activity, including the prevention and treatment of pre- and post ulceration symptoms and conditions, of the polyvalent metal compounds. Effective anti-inflammatory compounds without the need of a prescription are preferred.
  • topical administration of nonsteroidal anti-inflammatory compounds and/or low-potency glucocorticoidal steroids such as hydrocortisone, hydrocortisone acetate, cortisone or cortisone acetate, without the addition of a polyvalent metal compound is also beneficial in preventing aphthous ulcers or herpes simplex lesions and in treating their pre-ulceration symptoms.
  • concentration of an anti-inflammatory compound in a liquid, semi-solid, or solid composition will be about 0.01 to about 2%, more preferably about 0.05% to about 0.5% weight by volume.
  • an effective amount of one or more polyvalent metal compounds is an amount of one or more polyvalent metal compounds that is effective to reduce or diminish the size of the lesion, ulcer and/or inflamed tissue area, shorten the time for relief from the symptoms, and/or cause a reduction in the symptoms of aphthous ulcers or herpes simplex lesions.
  • the methods of the present invention relieve pre-ulceration and pre-lesion symptoms as wells as ulcers, lesions, post- ulceration and post-lesion symptoms and conditions, including pain, inflammation, irritation, and discomfort, within about 5 to about 20 minutes after topical administration of the polyvalent metal compound(s) to the affected tissue.
  • the methods of the present invention heal or cause the ulcer, lesion or inflammatory bump to disappear within about 5 hours or about 8 hours to about 24 hours after topical administration of the polyvalent metal compound. This is in sharp contrast with conventional drug therapy. Resolution of pain and healing of aphthous ulcers and/or herpes simplex lesions by conventional methods of treatment generally requires several days of continuous (3-to-4-times-a-day) treatment. It is emphasized that the surprising and unexpected efficacy of polyvalent metal compounds for the prophylaxis, treatment and/or cure of aphthous ulcers and herpes simplex lesions described herein can be attributed to the hitherto unreported combined effects of their analgesic, anti-inflammatory, anti-microbial and tissue-regenerating properties.
  • Pepto-Bismol ® (Proctor and Gamble, Cincinnati, Ohio) is a commercial nonprescription suspension product containing 262 mg of bismuth subsalicylate per tablespoon (15 ml) as the active ingredient (i.e., 1.75%).
  • the product label for Pepto-Bismol ® states that its recommended use is for the treatment of upset stomach, indigestion, nausea, heartburn and diarrhea.
  • the normal dose for adults is 30 ml, which may be repeated every 0.5 to 1.0 hour for a total of 8 doses (i.e., 240 ml) in one day.
  • Pepto-Bismol ® Prior to bedtime, a small amount of Pepto-Bismol ® , which had been concentrated through evaporation, was administered several times to the surface area of a painful aphthous ulcer (about 0.30 cm in size), which developed under a human tongue three days earlier. The following morning, there was no longer any pain associated with the lesion. The "concentrated" Pepto-Bismol ® was administered twice more that day, after which, the lesion was healed. The concentrated Pepto-Bismol ® suspension has also been used to quickly reverse further development of the early (no visible exudate) stages of aphthous ulcers.
  • a water-based oral paste A containing 1% bismuth citrate as an active ingredient was prepared.
  • the paste also contained about 30% glycerin, 1% sodium bicarbonate, 1% Carbopol ® ULTREX-10 (a polyacrylic acid polymer used as a thickening, bioadhesive or mucoadhesive agent) and 63% water.
  • the paste was administered to two inflammatory, painful bumps around the tongue and to a painful lesion on the floor of the oral cavity after drying these areas with clean tissue paper before bedtime. The pain literally stopped in a few minutes, and almost complete healing was noted the next morning.
  • Example III Treatment of Pre-Ulceration Symptoms and Prophylaxis of Aphthous Ulcers Using Bismuth Citrate and Naproxen Oral Paste
  • a water-based paste containing 1% bismuth citrate and 0.5% sodium naproxen with sodium carboxymethylcellulose as a thickening agent was prepared. A small amount of this paste was administered before bedtime to two aphthous ulcers of the tongue at the onset of development. The following morning, there were no longer any symptoms of the disease, and no further administration was needed. This novel treatment regimen was repeated successfully two more times.
  • Example IV Treatment of Pre-Ulceration Symptoms and Prophylaxis of Aphthous Ulcers Using Bismuth Citrate and Naproxen Oral Paste
  • a water-based oral paste containing about 0.6% bismuth citrate, 0.8% hydrocortisone, 27% glycerin, 61% water and 11% Carbopol ® ULTREX- 10 was prepared. Prior to bedtime, the area surrounding a small aphthous ulcer on the tip of a human tongue was dried with a cotton tip. Next, a small amount of the oral paste was administered to the lesion and the surrounding area. The following morning, there were no longer any symptoms of the disease.
  • the oral paste as described in Example IN, was administered prior to bedtime. The next morning, the gum was no longer bleeding. After further administration (twice a day for two days), the redness of the surrounding gingiva disappeared, the color returned to normal, and the size of the lesion was found to be approximately reduced by half (from about 0.4 mm to about 0.2 mm in length). Furthermore, after administration of the oral paste for three more days there was no pain or bleeding after probing the affected area with a toothpick. Additionally, the depth of the lesion appeared to be markedly reduced, and the affected area looked much healthier. Administration of medicament was facilitated by using a stainless spatula.
  • a lower strength of bismuth citrate (0.2%) and hydrocortisone (0.2%) oral paste B was also prepared similar to that described in Example U.
  • a small amount of oral paste B was administered to an aphthous ulcer on the tip of a human tongue, after drying the affected lesion area with tissue paper, prior to bed. The pain stopped almost immediately. The next morning, the ulcer, and its associated pain, were no longer present.
  • Oral paste B was administered two times a day to an area of gingivitis in a human for three days. After administration of this treatment, the gingival color returned to normal and the area no longer bled upon probing.
  • Oral paste C containing 0.25% aluminum hydroxide and 0.25% magnesium hydroxide was prepared similar to that of above oral paste B. After drying the tip of a human tongue with clean tissue paper, a small amount of oral paste C was administered to an area of demonstrating early signs (pre-ulcer stage) of a canker sore area before going to bed. The pain disappeared in a few minutes after administration. The inflammatory bump disappeared by the next morning. Similar results were obtained on other occasions.
  • Example X Treatment of Aphthous Ulcer with Zinc Acetate Oral Paste D Oral paste D containing 0.25% zinc acetate was prepared similar to that of oral paste B. A stinging pain with a small ulcer was noticed under the tongue of a human subject. At midnight, after drying the area with a clean paper tissue, a small amount of oral paste D was administered to the lesion and the pain stopped almost immediately. No pain was felt and the lesion was practically healed next morning. It is to be noted that administration of a placebo oral paste had no effect on relieving pain of the canker sore.
  • Example XI Treatment of Aphthous Ulcer with Zinc Acetate Oral Paste D Oral paste D containing 0.25% zinc acetate was prepared similar to that of oral paste B. A stinging pain with a small ulcer was noticed under the tongue of a human subject. At midnight, after drying the area with a clean paper tissue, a small amount of oral paste D was administered to the lesion and the pain stopped almost immediately. No pain was felt and the lesion was practically
  • Oral paste E containing about 0.25% aluminum potassium sulfate (i.e., alum) was prepared similar to oral paste B. The pH was adjusted to 4.8 with sodium carbonate. A painful bump (early stage of a canker sore) was noted in the right front edge of the tongue of a human subject. Oral paste E was administered to the affected area before bedtime. The pain from the pre- ulcerous symptom stopped within a few minutes after administration of Oral paste E. Next morning, the paste was administered two more times. The bump and pain disappeared before noon.
  • Oral paste F containing 0.5% anhydrous magnesium sulfate was similarly prepared as oral paste E.
  • a sizable red bump (pain upon touch) on the tongue of a human subject was treated with oral paste F before bedtime. The bump disappeared by the next morning.
  • Similar pastes containing 1% or 4% magnesium sulfate were also found to be similarly effective after one application prior to bedtime.
  • Oral paste G containing 0.15% ferric citrate was similarly prepared as oral paste E.
  • a single administration of oral paste G before bedtime was found to effectively treat the bump on a tongue on two occasions in a human subject.
  • a 4.0% magnesium sulfate paste (the pH was adjusted to about 6.0 with sodium hydroxide) with Carbopol ® 974P as a mucoadhesive agent was prepared and applied to an about 0.5cm size of aphthous ulcer on left top side of the tongue in a human subject before bedtime. The pain disappeared in about 15 minutes and no pain was felt the next morning. After eating breakfast, the paste was applied again and the aphthous ulcer was completely healed after the second application.
  • Oral paste I containing 3.0% magnesium sulfate and 0.2% hydrocortisone acetate with Carbopol 974P (BF Goodrich, Cleveland, OH) was prepared.
  • a human patient developed two painful medium-sized aphthous ulcers, one on the top surface of the tongue and the other underneath the tongue. The pain severely affected the eating and talking capabilities of the patient.
  • Oral paste I was applied before dinner to both ulcerous areas. The pain completely disappeared within about 20 minutes and the patient was able to talk and eat throughout dimier without any pain. Oral paste I was applied again prior to bedtime.
  • Oral paste I was also used to completely heal a small erythematous (e.g., redness of the mucosal tissue of the oral cavity caused by dilatation and congestion of the capillaries) bump with only one application prior to bed.
  • erythematous e.g., redness of the mucosal tissue of the oral cavity caused by dilatation and congestion of the capillaries
  • the safety of the above paste is obvious from the fact that both magnesium and hydrocortisone are endogenous substances and the amounts of the drugs present in the paste is minute compared to those normally present in the human body.
  • a paste containing 0.5% magnesium sulfate, 1% alum and 0.2% bismuth citrate was similarly prepared. The paste was applied two to three times a day to a he ⁇ es simplex lesion on a human subject. After application, no pain was noticed and the lesion completely healed in about 3 days.
  • a paste containing 0.02% of hydrocortisone or hydrocortisone acetate using Carbopol® as a mucoadhesive agent was also similarly prepared. In one patient, these pastes have been repeatedly demonstrated to almost immediately (within about 10 to 20 minutes) and completely relieve the pain of inflammatory bumps or lesions after one single application before bedtime. Furthermore, the bumps were found to disappear next day following one additional application in the morning. No development of more serious aphthous ulcers occurred later.
  • the strength of the steroid used above is much less than that (usually 0.1%) of high-potency steroids, such as triamcinolone acetonide, used conventionally; the strength employed is regarded as the "subtherapeutic" sfrength based on conventional steroid therapy..
  • a human subject had a percutaneous fissure or crack (about 1 cm long and about 0.2 cm wide) in the lower leg.
  • a 1% magnesium sulfate paste was applied to the fissure and covered with a bandage before bedtime. The pain completely disappeared and the fissure was completely healed (re- epithelialization) by the morning.

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Abstract

La présente invention concerne un procédé topique permettant d'exercer un effet analgésique, anti-inflammatoire et anti-microbien et une action de régénération des tissus pour prévenir et traiter avec efficacité les ulcérations aphteuses et les lésions dues à l'herpès ainsi que pour traiter avec efficacité les brûlures et les autres ulcères de la muqueuse orale. Ce procédé consiste à administrer par voie topique au tissu affecté une quantité efficace d'une composition comprenant un ou plusieurs composés métalliques polyvalents, comme du sulfate de magnésium, de préférence, avec un ou plusieurs composés anti-inflammatoires sûrs et efficaces comme de l'acétate d'hydrocortisone à ultra faible dosage, qui renforcent l'action des composés métalliques polyvalents. Les fractions ioniques et neutres des métaux polyvalents sont pharmacologiquement actives ; Les composés métalliques polyvalents solubles à l'eau et insolubles à l'eau présentent une efficacité thérapeutique.
EP02739785A 2001-06-07 2002-06-07 Compositions et procedes pour la prophylaxie et le traitement des ulceres aphteux et des lesions dues a l'herpes Withdrawn EP1531837A4 (fr)

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EP1531837A4 (fr) 2006-11-15
JP2005533047A (ja) 2005-11-04
KR20050007585A (ko) 2005-01-19
CN1627951A (zh) 2005-06-15
WO2003103691A1 (fr) 2003-12-18
US20050186288A1 (en) 2005-08-25
CA2484514A1 (fr) 2003-12-18
RU2004137651A (ru) 2005-10-10

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